The present invention relates to N-acyl-1,2,3,4-tetrahydroisoquinolines and to pharmaceutical compositions containing such compounds, for use in the treatment and prevention of atherosclerosis.
Atherosclerotic coronary heart disease represents the major cause for death and cardiovascular morbidity in the western world. Risk factors for atherosclerotic coronary heart disease include hypertension, diabetes mellitus, family history, male sex, cigarette smoking and serum cholesterol. A total cholesterol level in excess of 225-250 mg/dl is associated with significant elevation of risk.
Cholesterol esters are a major component of atherosclerotic lesions and the major storage form of cholesterol in arterial wall cells. Formation of cholesterol esters is also a key step in the intestinal absorption of dietary cholesterol. The intracellular esterification of cholesterol is catalyzed by the enzyme acyl CoA:cholesterol acyl transferase (ACAT, EC 2.3.1.26). Thus, inhibition of ACAT is likely to inhibit the progression of atherosclerotic lesion formation, decrease the accumulation of cholesterol esters in the arterial wall, and block the intestinal absorption of dietary cholesterol.
A number of N-acyl-1,2,3,4-tetrahydroisoquinoline enzyme inhibitors are known. U.S. Pat. Nos. 4,743,450, 4,634,715, 4,555,503 and European patent publication 259,838 disclose N-acyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid inhibitors of angiotensin I converting enzyme (ACE).
U.S. Pat. No. 4,460,775 discloses N-acyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid derivative ACE inhibitors.
German patent application DE 3,324,744 discloses N-acyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ACE inhibitors.
U.S. Pat. No. 4,729,985 discloses N-acyl-1,2,3,4-tetrahydroisoquinoline renin inhibitors of the formula: ##STR2## wherein R is H or methyl; R.sup.1 is phenyl, 1-naphthyl, 4-hydroxyphenyl, propyl, iso-propyl, 4-imidazolyl and 4-methoxyphenyl; and R.sup.2 is H, lower alkyl, lower alkoxy, phenyl or R.sup.3 -substituted phenyl wherein R.sup.3 is (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy, fluoro or chloro.
In addition, Chem. Abstracts 82(9): 57976v, by Stenlake, et al, discloses an N-acyl-1,2,3,4-tetrahydroisoquinoline having the structure: ##STR3##